Heretofore, a number of compounds have been synthesized which have a 2-substituted oxyiminoacetamide group as a side chain at the 7-position of the cephem nucleus. For example, there may be mentioned a 2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetamide group, a 2-(2-aminoxazol-4-yl)-2-substituted oxyiminoacetamide group, a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-substituted oxyiminoacetamide group, a 2-(furyl-2-yl)-2-substituted oxyiminoacetamide group or a 2-substituted phenyl-2-substituted oxyiminoacetamide group. As publications which disclose such compounds, for example, Japanese Unexamined Patent Publications No. 52083/1975, No. 102293/1977, No. 116492/1977, No. 137988/1978, No. 154786/1979, No. 157596/1979, No. 154980/1980, No. 86187/1981, No. 59895/1982, No. 99592/1982, No. 158769/1982, No. 192394/1982, No. 8087/1983 and No. 174387/1983, and The Chemical Society of Japan, Vol. 5, p.785-805 (1981), may be mentioned. It is disclosed that such compounds exhibit antibacterial activities against Gram-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa thus suggesting that they have excellent antibacterial activities and a broad antibacterial spectrum.
In addition to the above publications, as the prior arts concerning the present invention, Japanese Unexamined Patent Publications No. 9296/1979, No. 162592/1983, No. 108792/1984, No. 130294/1984, No. 34972/1985, No. 67483/1985 and No. 97982/1985, may be mentioned. In the claims of such publications, as substituents of the 2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetamide group at the 7-position of the cephem nucleus, a number of substituents are mentioned including an alkyl group and an alkenyl group. Further, the description of the alkenyl group is general referring, for example, to an alkenyl group which may be substituted, or a substituted unsubstituted C.sub.2 -C.sub.8 alkenyl group. However, the alkenyl group suggested by the specific disclosure and examples in the specifications is an unsubstituted alkenyl group such as a vinyl group or an allyl group. Further, as the alkenyl group substituted by a carboxyl group, there is only a 1-carboxylate allyl group, and there is no disclosure or suggestion concerning the 1-carboxy-1-vinyl group in the above prior art references. Further, with respect to the prior art relating to intermediates, a number of 2-substituted oxyiminoacetic acid derivatives have been synthesized as the acyl side chain acid at the 7-position of the cephem nucleus. As such an acyl side chain acid, for example, a 2-(2-aminothiazol-4-yl)-2-substituted oxyiminoacetic acid, a 2-(thiazol-4-yl)-2-substituted oxyiminoacetic acid, a 2-(2-aminooxazol-4-yl)-2-substituted oxyiminoacetic acid, a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-substituted oxyiminoacetic acid, a 2-(furyl-2-yl)-2-substituted oxyiminoacetic acid or a 2-(substituted phenyl)-2-substituted oxyiminoacetic acid, may be mentioned. As the publications describing such 2-substituted oxyiminoacetic acid compounds, for example,
Journal of the Japanese Chemical Society, p.785-804 (1981), the J. of Antibiotics, Vol. 34, p.1447-1455 (1981), ditto Vol. 35, p.712-720 (1982), ditto Vol. 36, p.1205-1210 (1983), ditto Vol. 37, p.532-571 (1984) and ditto Vol. 39, p.111-127 and p.404-414 (1986) may be mentioned. As the substituents of such substituted oxyimino groups, for example, lower alkyl, lower alkenyl, lower alkynyl, aralkyl and aryl groups which may have one or more substituents such as a hydroxyl group, a carboxyl group, a carbamoyl group, a cyano group, an amino group, a halogen atom, an alkyl group and an aryl group, are generally known.
Further, a 2-(1-vinyloxyimino)acetic acid derivative having a vinyl group as a substituent of the substituted oxyimino group is described in Japanese Unexamined Patent Publication No. 22392/1979 (corresponding to Ger. Offen., 2,831,332; Chem. Abstr., 90-168630n), and synthesized as shown by the following reaction scheme. ##STR3## In the formulas, X is a chlorine atom, a bromine atom or an iodine atom and alk is an alkyl group having from 1 to 4 carbon atoms.
This publication discloses only the 2-(1-vinyloxyimino)acetic acid derivative, and no synthesis or suggestion for a 2-(1-carboxy-1-vinyloxyimino)acetic acid derivative of the present invention is given.
.beta.-lactam antibiotics exhibit selective toxicity only against bacteria and give no substantial affects against animal cells, and they have been widely used for the treatment of infectious diseases caused by bacteria, as antibiotics having no substantial side effects. Thus, they are highly useful drugs. However, in recent years, the isolating frequency of resistant Gram-positive bacteria and resistant glucose non-fermentative Gram-negative rods, as causative organisms tends to increase. Therefore, it is desired to increase the activities of antibiotics against such bacteria.
It is an object of the present invention to provide novel cephalosporin derivatives having excellent antibacterial activities. Various cephalosporin derivatives have been synthesized which have a 2-substituted oxyiminoacetamide group at the 7-position of the cephem nucleus. With respect to a compound having a 1-carboxy-1-vinyloxyimino group as such substituted oxyimino group, however, there is no disclosure in patent specifications, not to mention its synthesis.
Namely, the compound of the present invention having a 2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetamide group at the 7-position of the cephem nucleus is a novel compound not disclosed in literatures. The present inventors have found that the compound of the present invention have strong antibacterial activities against sensitive or resistant Gram-negative bacteria and Gram-positive bacteria and excellent stability against .beta.-lactamase. The present invention has been accomplished on the basis of the discovery.
Further, the present inventors have conducted extensive researches to develop 2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-vinyloxyimino)acetic acid derivatives and a process for their production. As the results, it has been found that when the 2-(2-aminothiazol-4-yl)glyoxylic acid derivative of the formula VI is reacted with 0-(1-carboxy-1-vinyl)hydroxylamine derivative of the formula V, and if necessary, the protecting group is removed, it is possible to obtain the compound of the present invention having the formula III in good yield. The present invention has been accomplished on the basis of the discovery.